dbSNP rs370561885: PBX1:p.Gly38Glu (chr1-164559935-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_002585.4(PBX1):c.113G>A(p.Gly38Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,547,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

PBX1
NM_002585.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.93

Publications

2 publications found

Variant links:

Genes affected

PBX1 (HGNC:8632): (PBX homeobox 1) This gene encodes a nuclear protein that belongs to the PBX homeobox family of transcriptional factors. Studies in mice suggest that this gene may be involved in the regulation of osteogenesis and required for skeletal patterning and programming. A chromosomal translocation, t(1;19) involving this gene and TCF3/E2A gene, is associated with pre-B-cell acute lymphoblastic leukemia. The resulting fusion protein, in which the DNA binding domain of E2A is replaced by the DNA binding domain of this protein, transforms cells by constitutively activating transcription of genes regulated by the PBX protein family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2017]

PBX1 Gene-Disease associations (from GenCC):

congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

PBX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the PBX1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.8266 (above the threshold of 3.09). Trascript score misZ: 4.2973 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay.

BP4

Computational evidence support a benign effect (MetaRNN=0.01794511).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000197 (3/152142) while in subpopulation AMR AF = 0.000131 (2/15284). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002585.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PBX1	NM_002585.4	MANE Select	c.113G>A	p.Gly38Glu	missense	Exon 1 of 9	NP_002576.1	P40424-1
PBX1	NM_001204963.2		c.113G>A	p.Gly38Glu	missense	Exon 1 of 9	NP_001191892.1	P40424-3
PBX1	NM_001204961.2		c.113G>A	p.Gly38Glu	missense	Exon 1 of 8	NP_001191890.1	Q53YC7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PBX1	ENST00000420696.7	TSL:1 MANE Select	c.113G>A	p.Gly38Glu	missense	Exon 1 of 9	ENSP00000405890.2	P40424-1
PBX1	ENST00000367897.5	TSL:1	c.113G>A	p.Gly38Glu	missense	Exon 1 of 8	ENSP00000356872.1	P40424-2
PBX1	ENST00000627490.2	TSL:2	c.113G>A	p.Gly38Glu	missense	Exon 1 of 9	ENSP00000485692.1	P40424-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000463

AC:

AN:

151082

AF XY:

0.0000126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000573

AC:

AN:

1395406

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31422

American (AMR)

AF:

0.000227

AC:

AN:

35236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24926

East Asian (EAS)

AF:

0.00

AC:

AN:

35402

South Asian (SAS)

AF:

0.00

AC:

AN:

78734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077040

Other (OTH)

AF:

0.00

AC:

AN:

57812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.096

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.020

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

7.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.78

REVEL

Benign

0.29

Sift

Benign

0.45

Sift4G

Benign

0.21

Polyphen

0.036

Vest4

0.47

MVP

0.50

MPC

0.17

ClinPred

0.085

GERP RS

3.6

PromoterAI

0.18

Neutral

(source)

Varity_R

0.14

gMVP

0.40

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over